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molecular basis of disease > Haemolytic anaemias > Flashcards

Haemolytic anaemias Flashcards

1
Q

Define anaemia

A

reduced haemoglobin level for the age and gender of the individual

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2
Q

What are classification of anaemias?

A
  1. on the basis of cause => blood loss, inadequate production, excessive destruction of blood cells
  2. on the basis of morphology=> normocytic, microcytic and macrocytic
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3
Q

what is haemolytic anaemia?

A
  • anaemia due to shortened RBC survival (due to excessive breakdown of RBC)
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4
Q

What is normal RBC lifecycle?

A
  • 2x10^11 RBC/ day in the bone marrow
  • circulate for approx 120 days
  • 300 miles travelled through microcirculation
  • senescent RBC removed by RES
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5
Q

What happens in haemolysis life cycle?

A
  • shortened RBC survival 30-80 days
  • increase production By bone marrow to compensate
  • this leads to increased young cells in circulation = reticulocytosis +/- nucleated RBC
  • However RBC production unable to keep up with decreased RBC life span = decreased Hb
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6
Q

What are clinical findings?

A
  • jaundice
  • pallor
  • fatigue
  • splenomegaly
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7
Q

What are chronic clinical findings?

A
  • gallstones - pigment
  • leg ulcers
  • folate deficiency (increased use to compensate for loss RBC)
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8
Q

What do lab investigation for HA show?

A
  • peripheral blood film : polychromatophilia, nucleated RBC, thrombocytosis , neutrophilia with left shift;
  • morphologic abnormalaties provide clue to underlying disorder, ie: spherocytes, sickle cell, target cells, schistocytes, acathocytes.
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9
Q

What are bone marrow findings in lab investigation for HA?

A

compensatory mechanism to haemolysis

  • > erythroid hyperplasia of BM - with normoblastic rxn, reversal of M: E ration
  • > reticulocytosis - variable
  • mild (2-10%) hemoglobinopathies
  • moderate to marked (10-60%) , seen in these conditions: IHAS, HS , G6PD def.
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10
Q

What are other findings in lab investigation of HA?

A
  • increased unconjugated bilirubin
  • increased LDH (Lactate dehydrogenase)
  • Decreased serum haptoglobin protein that binds free Hb
  • incresed urobilinogen
  • increased urinary hemosiderin
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11
Q

What are classifications of haemolytic anaemia?

A
  1. inheritance
    - hereditary
    (hereditary spherocytosis)
    -acquired ( IHA)
  2. site of RBC destruction
    - intravascular (hemolytic transfusion Rxn)
    - extravascular (autoimmune haemolysis)
  3. Origin of RBC damage
    - intrinsic aka intracorpuscular (G6PD deficiency)
    - extrinsic aka extracorpuscular (infection)
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12
Q

What are the site of RBC destruction?

A 
1. extravascular (normal)
unconjugated bilirubin
->liver ->gut -> kidney 
2. intravascular (abnormal)
Hb -> kidney
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13
Q

What 2 conditions does defect in the membrane protein of RBC lead to?

A
  1. heriditary spherocytosis
    - autosomal dominant
    - caused by defects in vertical interactions
  2. hereditary elliptocytosis
    - defects in the horizontal interactions
    - loss of interaction between a and b spectrin.
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14
Q

What are clinical features of heriditary spherocytosis?

A
  • neonatal jundice
  • asymptomatic to severe haemolysis
  • splenomegaly
  • pigment gallstones
  • reduced eosin-50 maleimide (EMA) binding -binds to band 3
  • positive family history
  • negative direct antibody test
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15
Q

What is the role of hexose monophasphate shunt (HMP)?

A
  • generate NADPH and reduced Glutathione

- protects the cell from oxidative stress

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16
Q

What is the effects of deficiency of HMP?

A

oxidative stress

  • oxidation of Hb by oxidant radicals resulting in denatured Hb aggregates and forms heinz bodies
  • oxidised membrane = proteins reduced RBC deformability
17
Q

What is the function of pyruvate kinase pathway?

A
  1. glycolytic pathway = generates energy in ATP
    -to maintain red cell shape and deformability
    -to regulate intracellular cation conc. via cation pump(Na/K pump)
    =>defects in this pathway leads to defects in the RBC shape and deform ability
    Deformability important to allow RBC to squeeze through vessels
18
Q

What are 2 globin disorders?

A
  1. Thalassaemia - quantitative
    - defect in the rate of synthesis of alpha - beta globin chain (structurally normal)
  2. variant haemoglobins - qualitative
    - production of structurally abnormal globin chain
19
Q

What are thalassaemias?

A
  • imbalanced alpha and beta chain production
  • excess unpaired globin chains are unstable
  • heterogenous disorder
  • ineffective erythropoiesis
20
Q

What are thalassaemias clinically divided into?

A
  1. hydrop foetalis (alpha)
  2. beta thalassaemia
  3. thalassaemia intermedia
  4. thalassaemia minor
21
Q

Alpha thalassaemia

A

Hb barts hydrops syndrome

  • deletion of all 4 globin gene
  • incompatible with life

HbH disease
-deletion of 3/4 alpha globin genes
-common in SE asia
=>clinical features:
-moderate chronic HA, splenomegaly, hepatomegaly
-hypochromic microlytic, poikilocytosis, poly chromasia, target cells.
-electropherosis diagnostic

Trait minor:

  • normal or mild HA
  • MCV and MCH low
22
Q

Beta thalassaemia major

A

clinical features:

  • severe anaemia
  • progressive hepatosplenomegaly
  • bone marrow expansion - facial bone abnormalities
  • mild jaundice
  • iron overload
  • intermittent infections

peripheral blood

  • microcytic hypochromic with decreased MCV, MCH, MCHC
  • anispoikilocytosis, target cells, nucleated RBC, tear drop cells
  • reticulocytes >2%
23
Q

Thalassemia intermedia

A

disorder with clinical manifestation between major and minor

  • transfusion independent
  • diverse clinical phenotype
  • varying symptoms
  • increased bilirubin level
  • diagnosed -largely clinical
24
Q

Thalassemia minor

A
  • asymptomatic
  • often confused with Fe deficiency
  • a- thal trait often by exclusion
  • HbA2 increased in beta thal trait
25
Q

What is sickle cell disease?

A

-refers to all disease as a result of inherited HbS

26
Q

What causes SCD?

A

=>HbS is caused by a single nucleotide substitution.

  • HbSS = sickle cell anemia (homozygous)
  • HbAS = Sickle cell trait (heterozygous)

point mutation in beta globin gene glutamic acid -> valine at position 6.
insoluble Hb tetramer when deoxygenated -> polymerisation = sickle cell shape

27
Q

Clinical features of SCD

A
  • painful crises
  • aplastic crises
  • infections
  • acute sickling =chest syndrome, splenic detach, stroke
  • chronic sickling effect = renal failure, avascular necrosis
28
Q

Lab feature of SCD

A
  • anaemia : 60 to 90 Hb
  • reticulocytosis
  • increased NRBC
  • raised bilirubin
  • low creatine
29
Q

How do you confirm sickle cell diagnosis?

A

=> soluability test

  • exposure blood to reducing agent
  • HbS precipitated
  • positive in trait and disease
30
Q

features of hemolysis

A
  • jaundice
  • pallor
  • splenomegaly
  • reticulocytosis
  • unconjugated hyperbillirubinaemia
  • raised LDH
31
Q

Hemolytic anemia can be classified into intrinsic and extrinsic, what does intrinsic anemia include?

A
  1. Membrane defects
  2. Enzyme defects
  3. Hemoglobin defects
32
Q

What two categories can extrinsic HA be divided into?

A
  1. Immune mediated
    - autoimmune
    - alloimmune
  2. Non immune
    - RBC fragmentation
    - mechanical trauma
    - drugs and chemicals

molecular basis of disease (29 decks)

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